Intermediate in the total synthesis of elenolic acid

ABSTRACT

A COMPOUND OF THE FORMULA:   2-R4,2-R5,5-R1,8-(R2-CH(-COO-R)-)-3A,4,7,7A-TETRAHYDRO-   4,7-METHANO-1,3-BENZODIOXOLE   WHEREIN R IS ALKYL OF 1 TO 8 CARBON ATOMS, INCLUSIVE, R1 IS ALKYL OF 1 TO 4 CARBON ATOMS, R2 IS HYDROGEN OR ALKYL OF 1 TO 4 CARBON ATOMS, AND R4 AND R5 ARE HYDROGEN, ALKYL OF 1 TO 4 CARBON ATOMS, INCLUSIVE OR PHENYL, WITH THE PROVISO THAT ONLY ONE OF R4 AND R5 IS PHENYL, IS PRODUCED IN A MULTISTEP REACTION. THE COMPOUND IS AN INTERMEDIATE FOR ELENOLIC ACID.

United States Patent Oflice 3,786,068 Patented Jan. 15, 1974 3,786,068INTERMEDIATE IN THE TOTAL SYNTHESIS OF ELENOLIC ACID Robert C. Kelly,Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. NoDrawing. Original application Aug. 24, 1970, Ser. No. 66,557, now PatentNo. 3,703,530, dated Nov. 21, 1972. Divided and this application Apr.12, 1972, Sex.

Int. Cl. com 13/10 US. Cl. 260-3405 2 Claims ABSTRACT OF THE DISCLOSUREA compound of the formula:

COOR

i Rz'CH This application is a divisional application of application Ser.No. 66,557, filed Aug. 24, 1970, now Pat. No. 3,703,530, issued Nov. 21,1972.

BACKGROUND OF THE INVENTION (1) Field of the invention The presentinvention is concerned with a process for the synthesis of elenolicacid, analogs and derivatives thereof and with the intermediates in saidprocess.

(2) Description of the prior art Already in 1931 A. D. Burnett and M.Oliviero [Bull. Ace. Md., 122, 191 (1931)] recognized that an extractfrom the leaves of the olive tree (Olea europaea) contained ahypotensive principle [see also L. Panizzi et al., Gazz. Chim. Ital.,90, 1449 (1960)].

W. L. Constantijn Veer, 'U.S. Pat. 3,033,877, issued May 8, 1962,described the preparation of elenolic acid, salts, ether-esters andother analogs of elenolic acid. The only method for the preparation ofthis acid, salts or derivatives thereof was by extraction and chemicaltreatment of the extractives of the leaves or the fruit of Oleaem'opaea. In particular the aqueous press juice resulting from pressingthe ripe fruit was used. The amount of acid obtained was alwaysexceedingly small; e.g., US. Pat. 3,033,877 reports that from 250 kg. ofleaves of Olea europaea 114 g. of an impure oil was obtained concerningwhich it was stated consists for the greater part of elenolic acid. Thesame patent reports that from 160 liters of press juice 0.35 g. ofelenolide (lactone form of elenolic acid) was obtained.

The Upjohn Company from a batch of 37,000 liters of olive press juice(obtained in Spain) isolated 1,300 g. of highly purified calciumelenolate, much purer than the material reported above. In addition, onthe basis of nuclear magnetic resonance, ultraviolet and infrared data,it was indicated that the older structures are not correct, and that themost likely structure of elenolic acid is:

0 CHr-COOH onto-i -030 OFCHS The present total synthesis of elenolicacid and its analogs is therefore a significant advance over thepreparation from the natural materials obtainable from the Europeanolive tree.

SUMMARY OF THE INVENTION The novel process of this invention and thenovel intermediates therein caq be illustratively represented by thefollowing sequence of formulae:

R. (A) R. Q 9 Siam VII wherein R and R are alkyl of 1 to 8 carbon atoms,inclusive, wherein R is alkyl of 1 to 4 carbon atoms, inclusive, whereinR is selected from the group consisting of hydrogen and alkyl of 1 to 4carbon atoms, inclusive, wherein R and R are selected from the groupconsisting of hydrogen, alkyl of 1 to 4 carbon atoms, inclusive, andphenyl, with the proviso that only one of R and R is phenyl, wherein Xis selected from the group consisting of bromine, iodine,benzenesulfonyloxy, alkanesulfonyloxy and alkylbenzenesulfonyloxy inwhich each alkyl moiety is of 1 to 4 carbon atoms, inclusive, andwherein X is the anion of an acid HX which can be easily removed as HXto form a temporary double bond, and wherein X is selected from thegroup consisting of those radicals represented by X and hydroxy.

The process of this invention comprises: reacting cyclopentadienyllithium, sodium, or potassium (I) with an alkylating agent of theformula 1 Xr-OH-C OR (A) wherein R, R and X are as given above, to givethe corresponding 1,3-cyclopentadiene-S-acetic acid alkyl ester (II);reacting II at low temperatures with an alkylmaleic anhydride (B) toobtain the corresponding 2,3-dicarboxy- -norbornene-7-acetic acid alkylester 2,3-anhydride (III); hydrolyzing III to obtain the corresponding2,3-dicarboxy- 5-norbornene-7-acetic acid alkyl ester (IV); treating IVwith osmium tetroxide, or wi h a chlorate salt and a catalytic amount ofosmium tetroxide, to obtain the corresponding2,3-dicarboXy-5,6-dihydroXynorbornane-7-acet1c acid alkyl ester (V);treating V with an aldehyde or ketone, preferably acetone, to obtain thecorresponding 2,3-d1- carboxy-5,6 dihydroxynorbornane 7-acet1c acid,alkyl ester, acetal or ketal (VI); subjecting VI to electrolys s in awater-pyridine solution containing 1 to 5% of a tertiary amine such astriethylamine to obtain the corresponding 5,6-dihydroxy-2 norbornene-7acetic acid, alkyl ester, acetal or ketal (VII); oxidizing VII withaqueous potassium permanganate and sodium periodate to give thecorresponding 2 alkanoyl-3,4-dihydroxy-5-carboxycyclopentaneacetic acid,alkyl ester, acetal or ketal (VIII); esterifying (VIII) with an alkanolin the presence of a dehydrating agent such as a carbodiimide or withdiazoalkane to obtain the corresponding 2-alkanoyl-3,4dihydroxy-5-carboxycyclopentaneacetic acid, 1,5-dialky1 ester, acetal orketal (IX) (the two alkyl groups 1 and 5 can be alike or different);reducing IX with an alkali metal borohydride to give the corresponding2-(l-hydroxyalkyl)-3,4-dihydroxy-S-carboxycyclopentaneacetic acid,1,5-dialkyl ester, acetal or ketal (X); converting X to a 2-ester, e.g.,the methanesulfonate of 2-(l-hydroxyalkyl)-3,4-dihydroxy-5-carboxycyclopentaneacetic acid 1,5-dialkyl ester, acetal or ketal (XI);treating XI with a dilute aqueous acid to give2-(l-hydroxyalkyl)-3,4-dihydroxy 5 carboxycyclopentaneacetic acid,1,5-dialkyl ester, 2-ester, e.g., Z-methanesulfonate (XII); oxidizingthe glycol XII with aqueous periodate salt to give the corresponding2-hydroXy-3-(lhydroxyalkyl)-5-carboxy-3,4-dihydro-2H-pyran 4-acet1cacid, 4,5-dialkyl ester, 3-ester (XIII); heating Compound XIII in abasic medium, pH 7.5 to 9, to give the corresponding Compound XIV, e.g.,methyl elenolate when R, R and R are methyl and R is hydrogen. CompoundXIV can be selectively hydrolyzed with dilute mineral acid to an acid ofFormula XV. If in Formula XV R and R are methyl and R is hydrogen, theacid is elenolic acid.

Alternatively, Compound X can be hydrolyzed with dilute aqueous acid togive Compound XII where X, is hydroxy.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The alkyl groups herein usedhaving from 1 to 4 carbon atoms, inclusive, such as R and R areillustratively methyl, ethyl, propyl, butyl, isobutyl, secondary butyland the like.

The alkyl groups herein used having from 1 to 8 carbon atoms, inclusive,comprise the group of alkyl groups above with up to 4 carbon atoms, andpentyl, hexyl, heptyl, and octyl and the branched isomers thereof.

The parameter X herein used is a negative element or group which isreactive in metathetic reactions with compounds containing a strongpositive element such as sodium, potassium or lithium. Such negativeelements or groups are illustratively iodine, bromine,methanesulfonyloxy, butanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy and the like.

The parameter X is a negative element or negative group which includesall groups and elements disclosed for X and also chlorine, and -OCOR inwhich R is selected from the group consisting of alkyl of 1 to 8 carbonatoms, inclusive, as illustrated above, and phenyl and p-tolyl.

Elenolic acid being of low stability is generally used only in the formof salts, such as the calcium salt, sodium salt or as an ester, e.g., asmethyl or ethyl elenolate. Such products Were known to be hypotensiveand were known to be useful in humans and animals as hypotensive agents(see U.S. Pat. 3,033,877). More recently it was discovered that calciumelenolate and other metal elenolates and esters of elenolic acid arehighly virucidal against Coxsackie A21 virus, polioviruses 1, 2, and 3,rhinovirus strain 209, parainfluenza-3 virus, herpes viruses, vacciniavirus, adenoviruses 1, 2, 3, and 7, respiratory syncitial virus,Newcastle disease virus and others.

5 Saline solution of 1 mg. per ml. of calcium elenolate reduced theviral activity (measured by the number of plaques of viruses present inthe sample) as follows:

Likewise, the compounds of Formulas XIII, XIV, and XV and salts thereofare virucidal and are thus useful to cleanse glassware, apparatus, andhospital equipment from virus contamination when used in solutions of0.1 to 5 parts per 1000 (weight) in the cleaning solution.

In carrying out the process of this invention a cyclopentadiene alkalimetal salt, e.g., cyclopentadienyl lithium, sodium, or potassium (I) isreacted with a negatively substituted alkyl acetate (A) as definedabove, e.g., methyl bromo-, iodo, or methanesulfonyloxyacetate, ethyl2-bromopropionate, and the like. The reaction is preferably carried outby adding to the cyclopentadiene alkali metal salt, in purifiedtetrahydrofuran, the substituted alkyl acetate, dropwise, in a nitrogenatmosphere, at a temperature of -10 to 30 C. However, temperaturesbetween and 50 C. are operative. Instead of tetrahydrofuran, diethyl,dipropyl, dibutyl ether, or mixed ethers can be used. An average of 70to 80% yield of 1,3-cyclopentadiene-S-acetic acid alkyl ester (II) isobtained, which is used in crude form in the next step.

Compound II in its crude form in tetrahydrofuran or an ether as statedabove is reacted with an approximately equimolar amount of alkylmaleicanhydride at a low temperature, between +5 and 30 C. The reaction periodis between 12 hours and 21 days. The thus-obtained product is isolatedby conventional procedure, e.g., evaporating the solvent, extraction,crystallization and combinations thereof and is purified by standardmethods such as crystallization, chromatography and the like to providethe corresponding 2,3-dicarboxy-5-norbornene-7-acetic acid alkyl ester2,3-anhydride (III).

Compound III is hydrolyzed in conventional manner, such as by heatingthe compound in aqueous 5% sodium or potassium bicarbonate solutionbetween to 60 min utes on the steam bath, and thereafter acidifying theresulting solution to a pH of 3. The product, a2,3-dicarboxy-S-norbornene-7-acetic acid alkyl ester (IV) precipitatesin the aqueous solution and can be easily collected on a filter.Purification of the product is best achieved by crystallizing theprecipitated product.

Compound IV is treated with an alkali metal or alkaline earth chloratesalt (e.g., sodium, potassium, calcium, or barium chlorate) and acatalytic quantity of osmium tetroxide. The reaction can be run inpartial suspension through the use of water as reaction medium or insolution through the use of mixed solvents such as water-tert. butylalcohol or water-tetrahydrofuran, and the like. In the preferredembodiment of this invention Compound IV is treated in a watersuspension with a 0.1 to 0.5 molar excess of chlorate salt and 0.2 to 1%by weight of osmium tetroxide. The temperature for the reaction ispreferably 40-50 C., but temperatures between 10 and 75 C. areoperative. The reaction time is between 2 and 100 hours and is ingeneral between 5 and 20 hours.

Compound IV can also be oxidized with osmium tetroxide alone, asillustrated in Example 8. The product of the foregoing oxidation, a2,3-d.icarboxy-5,6-dihydroxynorbornane-7-acetic acid alkyl ester (V) isgenerally iso lated by extraction and the product purified bycrystallization.

Compound V is treated with a large excess of an aldehyde or ketone,e.g., acetaldehyde, benzaldehyde, acetone, diethyl ketone, ethyl methylketone, dipropyl ketone, acetophenone, or the like in the presence of ananhydrous acid, e.g., hydrogen chloride or hydrogen bromide. In thepreferred embodiment of this invention, Compound V is treated with alarge excess of acetone, which acts as reagent and slurrying agent, inthe presence of 5 to 15% of 2,2-dimethoxypropane and 0.1 to 1% ofanhydrous hydrogen chloride. The reaction can be carried out attemperatures between 10 to 40 C. during a period of 15 to 120 minutes.The product, a 2,3-dicarboxy-5,6-dihydroxynorbornane-7-acetic acid,alkyl ester, acetal or ketal (VI) is isolated and purified byconventional procedures, e.g., extraction, crystallization,chromatography and the like.

Compound VI is electrolyzed in a basic medium, e.g., in pyridine-watermixtures with 1-5% (by volume) of trialkylamine present, e.g.,triethylamine or tributylamine, or heterocyclic tertiary amines such as1-methylpiperidine, 4-methylmorpholine, and1,4-diaza[2.2.2]bicyclooctane. The electrodes are preferably platinumand the voltage is held between 50 and 100 volts. The reaction mixtureis kept to 20 C. or less during the electrolysis. The electrolysis isadvantageously carried out by starting the electrolysis withapproximately 20% of the solution to be electrolyzed and then adding theremaining portion slowly so as to maintain the amperage at approximately4 for a voltage of and a temperature of 20 C. The total reaction time isbetween 4 to 6 hours. The thus-produced5,6-dihydroxy-2-norbornene-7-acetic acid, alkyl ester, acetal or ketal(VII) is isolated and purified, preferabl by chromatography,recrystallization, extraction, and the like.

Compound VII is oxidized within a pH range 6.0 to 8.5, with an aqueoussolution of permanganate and periodate salts, preferably sodium orpotassium permanganate and sodium or potassium periodate, with sodium orpotassium bicarbonate present. The oxidizing reagents are used in excessof the required stoichiometric amounts in aqueous concentration of 0.5to 10% (weight) of oxidant to water. The reaction is carried out attemperatures between 10 and 50 C. during a period of 1 to 8 hours,preferably with stirring. To avoid losses by additional undesiredoxidation reactions, the reaction when near completion is terminated byadding sodium sulfite until the permanganate color disappears. Theproduct is preferably isolated by extraction with an organicwater-immiscible solvent, e.g., chloroform, methylene chloride, benzeneor the like. The thus-obtained 2-alkanoyl-3,4dihydroxy-S-carboxycyclopentaneacetic acid, alkyl ester,acetal or ketal (VIII) can be purified by recrystallization.

The acid Compound VIII is esterified by conventional procedures, e.g.,with an alkanol and a dehydrating agent such as a carbodiimide, e.g.,dicyclohexylcarbodiirnide, a sulfonyl chloride, e.g., p-toluenesulfonylchloride, a chloroformate, e.g., isobutyl chloroformate, and the like,or with a diazoalkane in ether to give a dialkyl ester, 2alkanoyl-3,4-dihydroxy-S-carboxycyclopentaneacetic acid, 1,5-dialkylester, acetal or ketal (1X).

Compound IX is then selectively reduced with a metal hydride, preferablya metal borohydride such as lithium, sodium, or potassium borohydride.In the preferred embodiment of this invention, the borohydride is addedin portions over a short period, 10-30 minutes, to a solution of thediester IX in solution. Methanol, ethanol or ether are the preferredsolvents for Compound DC. The thusobtained Compound X, a2-(1-hydroxyalkyl)-3,4-dihydroxy-S-carboxycyclopentaneacetic acid,1,5-dialkyl ester, acetal or ketal, is isolated and purified byconventional procedures, e.g., extraction, chromatography,crystallization, and the like.

The hydroxy group of Compound X is then esterified, preferably withmethanesulfonyl chloride in pyridine solution at a low temperature, forexample, between +10 and l C. Other alkane-, alkylbenzeneandbenzenesulfonyl halides can be used, as well as alkanoyl, benzoyl, andp-toluoyl halides and anhydrides, or brominating and chlorinatingagents, e.g., N-bromosuccinimide, N-bromoacetamide, thionyl chloride andthe like. Extraction and recrystallization provide the corresponding2-(l-hydroxyalkyl)-3,4-dihydroxy 5 carboxycyclopentaneacetic acid,1,5-dialkyl ester, Z-methanesulfonate, acetal or ketal (XI) or otherFormula XI 2-ester.

Compound XI is converted to the corresponding 2-(1-hydroxyalkyl)-3,4-dihydroxy 5 carboxycyclopentaneacetic acid,1,5-dialkyl ester, 2-ester, e.g., 2-methanesulfonate (XII) by treatingit for 1 to 4 hours in aqueous formic acid or in aqueous sulfuric acid,hydrochloric acid or other dilute mineral acids, at a temperaturebetween and 50" 0., preferably at room temperature between 22 and 26 C.The product XII is recovered by evaporating the reaction mixture,freeze-drying or chromatography.

Compound XII is then treated with excess aqueous alkali metal periodatesalt, e.g., sodium or potassium periodate at a pH between 5 and 7 and ata temperature between and C. for 1 to 8 hours, usually from 2 to 4 hoursat room temperature and the reaction mixture is extracted with awater-immiscible solvent. The extract contains in solution thecorresponding 2-hydroxy-3-(1- hydroxyalkyl)-5-carboxy 3,4dihydro-2H-pyran-4-acetic acid, 4,5-dialkyl ester, 3-ester, e.g.,S-methanesulfonate (XIII). Compound XIII can be obtained by distillationof the solvent and purified by conventional procedures, e.g.,crystallization, chromatography, and the like.

Heating a mildly basic solution (preferably aqueous pyridine) containingCompound XIII at 90l00 C. for a period of 10 to 300 minutes gives a3-formyl-5-carboxy- 3,4-dihydro-2H-pyran-4-acetic acid 4,5 dialkyl ester(XIV). In the case that R, R and R are methyl and R is hydrogen theproduct XIV is methyl elenolate. Compound XIV is isolated byconventional procedures such as extraction, differential distribution ofthe product XIV in a solvent system, e.g., Craig extractor orchromatography.

Heating Compound XIV with dilute mineral acid, e.g., 0.1 M sulfuric acidgives 3-formyl-5-carbalkoxy-3,4-dihydro-2H-pyran-4-acetic acid (XV),which in case R and R are methyl and R is hydrogen is free elenolicacid.

The following preparation and examples illustrate this invention.

PREPARATION 1 (,yclopentadienyl sodium Metallic sodium (23 g.; 1 mole)was pressed into a fine ribbon and suspended in freshly purifiedtetrahydrofuran. A 100 ml. quantity of cyclopentadiene was added in oneportion and the mixture was stirred under nitrogen for minutes. Duringthat period a vigorous reaction occurred, warming the mixture to reflux.After this time an outside heat source was applied and the reactionmixture was heated under reflux an additional 2 hours. By this time allof the sodium had reacted. The cyclopentadienyl sodium is extremelysensitive to air and depending on the care with which the reaction wasrun, at this point it showed variation from near colorless through pinkto deep purple. The color did not seem to appreciably afiect the yields.

In the same manner given above cyclopentadienyl lithium or potassium canbe made,

8 EXAMPLE 1 Methyl 1,3-cyclopentadiene-S-acetate One mole ofcyclopentadienyl sodium, made up with tetrahydrofuran to 1 liter wascautiously transferred, under a nitrogen atmosphere, to a droppingfunnel and was then added dropwise over 1.5 hours to 304 g. (2.0 moles)of methyl bromoacetate cooled to 20 C. During the addition, the reactionmixture was maintained between 20 and 15 C. The crude reaction mixturewas used as such for the subsequent step. The product was analyzed bywithdrawing an aliquot, filtering and distilling the tetrahydrofuranfrom the aliquot filtrate at -10 C. under high vacuum. The residue wasquicky dissolved in deuterochloroform and an NMR taken. Analyses ofvarious runs of the reaction have indicated 70-80% of the desired isomer(methyl l,3-cyclopentadiene-S-acetate) and 30-20% of the l-isomer(methyl 1,3-cyclopentadienel-acetate).

NMR spectrum (CDCl 6): (a) 5-isomer=2.38 (2H, d, J=8.5 c.p.s.), 3.67(3H, s), 6.42 (4H, S); (b) 1- isomer=3.00 (2H, m), 3.44 (2H, m), 3.65(3H, s), 6.38 (3H, m).

The same product is obtained by replacing the cyclo pentadienyl sodiumwith cyclopentadienyl lithium or potassium.

EXAMPLE 2 Ethyl a-methyl-1,3-cyclopentadiene-S-acetate In the mannergiven in Example 1, cyclopentadienyl sodium was added to ethylot-bromopropionate to give ethyl a-methyl-l,3-cyclopentadiene-5-acetate.

In the same manner given in Example 1, other alkyll,3-cyclopentadiene-S-acetates and alkylu-alkyl-1,3-cyclopentadiene-S-acetates (II) can be made by reacting analkyl u-bromoalkanoate (A) with cyclopentadienyl anion. Representativecompounds, thus obtained, include:

propyl a-ethyl-1,3-cyclopentadiene-S-acetate, butyla-propyl-1,3-cyclopentadiene-S-acetate, pentylu-butyl-1,3-cyclopentadiene-S-acetate, hexyla-methyl-1,3-cyclopentadiene-5-acetate, heptyl1,3-cyclopentadiene-S-acetate, octyl 1,3-cyclopentadiene-S-acetate,isopropyl a-methyl-1,3-cyclopentadiene-S-acetate, isobutyla-propyl-1,3-cyclopentadiene-S-acetate, and the like.

EXAMPLE 3 Methyl 2,3-dicarboxy-2-methyl-5-norb0rnene-7- acetate2,3-anhydride The total crude reaction mixture containing methyl1,3-cyclopentadiene-S-acetate (Example 1) from a 1.5- mole run wastreated with 500 g. (4.4 moles) of citraconic anhydride. Afterdistillation of excess solvent at less than 10 C. and less than 1 mm,the reaction mixture was allowed to stand 14 days at 13 C. The reactionmixture was then partitioned between methylene chloride and water. Themethylene chloride solution was thoroughly washed successively with 5%aqueous sodium bicarbonate solution, water, and saturated brine. Themethylene chloride solution was then dried over anhydrous sodium sulfateand distilled in vacuo, leaving a viscous brown residue. Crystallizationof the residue from ether gave 147.5 g. of methyl2,3-dicarboXy-2-methyl-5- norbornene-7-acetate 2,3-anhydride of meltingpoint 103 C. There was obtained from the mother liquors a second cropamounting to 24.3 g.; melting point 90- 105 C.

A sample was prepared for analysis by one more crystallization frommethylene chloride-ether; melting point 105108 C.

Analysis.Calc. for C H O (percent): C, 62.39; H, 5.64. Found (percent):C, 62.28; H, 5.97.

NMR spectrum (CDCl;,, 6) 1.66 (3H, s), 2.41 (2H, A B), 2.6 (1H, AgB),3.0 (1H, m), 3.2 (1H, d, J=4 c.p.s.), 3.6 (1H, m), 3.65 (3H, s), 6.30(2H, AAXX').

EXAMPLE 4 Ethyl 2,3-dicarboxy-2-methyl-5-norbornene-7-acetate2,3-anhydride ethyl a-methyl-2,3-dicarboxy-Z-methyl-S-norbornene-7-acetate 2,3-anhydride,

propyl a-ethyl-2,3-dicarboxy-2-propyl-5-norbornene-7- acetate2,3-anhydride,

butyl a-propyl-2,3-dicarboxy-2-butyl-5-norbornene-7- acetate2,3-anhydride,

isopropyl u-butyI-Z,3-dicarboxy-Z-isobutyl-S-norbornene- 7-acetate2,3-anhydride,

isobutyl a-isobutyl-2,3-dicarboxy-2-isopropyl-5- norbornene-7-acetate2,3-anhydride,

hexyl u-propyl-2,3-dicarboxy-Z-methyl-S-norbornene- 7-acetate2,3-anhydride.

heptyl u-isopropyl-2,3-dicarboxy-2-methyl-5- norbornene-7-acetate2,3-anhydride,

octyl a-methyl-2,3-dicarboxy-Z-methyl-S-norbornene- 7-acetate2,3-anhydride,

pentyl 2,3-dicarboxy-2-ethyl-5-norbornene-7-acetate 2,3-anhydride,

isopentyl 2,3-dicarboxy-2-methyl-5-norbornene-7- acetate 2,3-anhydride,

methyl a-methyl-2,3-dicarboxy-2-methyl-S-norbornene- 7-acetate2,3-anhydride,

ethyl methyl-2,3-dicarboxy-2-butyl-5-norbornene-7- acetate2,3-anhydride,

and the like.

EXAMPLE 5 Methyl 2,3-dicarboxy-2-methyl-5-norbornene-7-acetate A 225 g.quantity of methyl 2,3-dicarboxy-2-methyl-5- norbornene7-acetate2,3-anhydride was added to 2 l. of Water. After stirring for 1 hour atreflux, the reaction mixture was filtered while still hot. On standingand coolini 192 g. of crystals were deposited; melting point 14=6148 C.A second crop of 14 g. was obtained; melting point 138-l41 C.

A sample was prepared for analysis by one more crystallization fromwater; melting point l51-l52 C.

Analysis-Cale for C H O (percent): C, 58.20; H, 6.01. Found (percent):C, 58.16; H, 6.10.

EXAMPLE 6 Ethyl 2,3-dicarboxy-2-methyl-5-norbornene-7-acetate In themanner given in Example 5, ethyl 2,3-dicarboxy- 2methyl-S-norbornene-7-acetate 2,3-anhydride was hydrolyzed in water togive ethyl 2,3-dicarboxy-2-methyl-5- norbornene-7-acetate.

In the manner given in Example 5, other alkyl2,3-dicarboxy-S-norbornene-7-acetate 2,3 anhydrides of Formula III, aslisted above can be hydrolyzed in water to give the corresponding alkyl2,3-dicarboxy-5-norbornene- 7-acetate. Products thus obtained, include:

ethyl a-methyI-Z,3-dicarboxy-2-methyl-5-norbornene-7- acetate,

propyl methyl-2,3-dicarboxy-2-propyl-5-norbornene-7- acetate,

butyl u-propyl-2,3-dicarboxy-2-butyl-5-norbornene-7- acetate,

isopropyl a-butyl-2,3-dicarboxy-2-isobutyl-5-norbornene- 7-acetate,

isobutyl isobutyl-2,3-dicarboxy-2-isopropy1-5-norbornene-7-acetate,

hexyl a-propyl-Z,3-dicarboxy-2-methyl-5-norbornene-7- acetate,

heptyl a-isopropyl-2,3-dicarboxy-Z-methyl-S-norbornene- 7-acetate,

octyl a-rnethyl-2,3-dicarboxy-Z-methyl-5norbornene-7- acetate,

pentyl 2,3-dicarboxy-Z-ethyl-5-norbornene-7-acetate,

pentyl 2,3-dicarboxy-2-methyl-5-norbornene-7-acetate,

methyl a-methyI-Z,3-dicarboxy-Z-methyl-S-norbornene-7- acetate,

ethyl methyl-2,3-dicarboxy-2-butyl-S-norbornene-7- acetate,

and the like.

EXAMPLE 7 Methyl 2,3-dicarboxy-2-methyl-5-norbornene-7-acetate In themanner given in Example 4, 1 mole of methyl1,3-cyclopentadiene-S-acetate was reacted with 340 g. of citraconicanhydride in tetrahydroifuran.

The tetrahydrofuran was removed by distillation in vacuo at -l0 C. Thereaction mixture was allowed to stand for 3 days at --l3 C. and 2 daysat --2 C. The mixture was then poured into 1 liter of water containing320 g. of sodium carbonate. The resultant mixture was cautiously heatedon a steam bath for 1 hour. It was then cooled, extracted with methylenechloride and then acidified with concentrated hydrochloric acid. Theprecipitated product was collected by filtration and Washed with Water.Crystallization of the product from water gave 38.0 g. of methyl2,3-dicarboxy-Z-methyl-S-norbornene- 7-acetate of melting point 150-151C. Second and third crops totaling 16.1 g. were obtained; melting point139- 143 C.

EXAMPLE 8 Methyl 2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornene- 7-acetate A 106 g. (0.396 mole) quantity of methyl 2,3-dicarboxyZ-methyl-5-norbornene-7-acetate was dissolved in 750 ml. oftetrahydrofuran and the resultant solution was treated with g. (0.394mole) of osmium tetroxide in 750 ml. of tetrahydrofuran. The mixture wasallowed to stand for three days at 25 C. The resultant black mixture wascooled in an ice bath, stirred and treated with excess hydrogen sulfidegas. The mixture was filtered free of solids. The filter cake was washedthoroughly with tetrahydrofuran. The filtrate and the washes werecombined and evaporated to dryness. Crystallization of the residue fromethyl acetate gave 63.8 g. of methyl 2,3- dicarboxy 5,6dihydroxy-Z-methylnorbornene-7-acetate as off-white crystals of meltingpoint 12l-127 C. There was obtained from the mother liquors a secondcrop amounting to 7.0 g. of product. Total yield 59% A sample Wasprepared for analysis by recrystallization from water; melting point122-126 C.

Analysis.-Calcd. for C H O (percent): C, 48.75; H, 6.29. Found(percent): C, 48.79; H, 6.42.

EXAMPLE 9 Methyl 2,3-dicarboxy-5,6-dihydroxy-Z-methylnorbornane-7-acetate A 5.0 g. (19 millimoles) quantity of methyl2,3-dicarboxy-2-methyl-5-norbornene-7-acetate was added to a solution of3.0 g. (24.5 millimoles) of potassium chlorate and 50 mg. of osmiumtetroxide in 125 ml. of water. The mixture Was warmed to 50 C. andstirred for hours. The reaction mixture was then cooled and extractedwith benzene. The aqueous layer was saturated with sodium chloride andextracted 3 times with tetrahydrofuran. The tetrahydrofuran solution wasdried over anhydrous magnesium sulfate and distilled in vacuo, leavingan oil. Crys tallization of the oil from ethyl acetate gave 1.95 g. ofmethyl 2,3-dicarboxy-5,6-dihydroxy-Z-methylnorbornane- 7-acetate;melting point 129130 C.

EXAMPLE 10 Ethyl 2,3-dicarboxy-5,-6-dihydroxy-2-ethylnorbornane-7-acetate In the manner given in Example 9, ethyl 2,3-dicarboxy-2-ethyl-5-norbornene-7-acetate was treated with osmium tetroxide intetrahydrofuran to give ethyl 2,3-dicarboxy-5,6-dihydroxy-2-ethylnorbornane-7-acetate.

In the manner given in Example 9, other alkyl2,3-dicarboxy-S,6-dihydroxy-Z-alkylnorbornane-7 acetates are produced bytreating the corresponding alkyl2,3-dicarboxy-2-alkyl-5-norbornene-7-acetates with osmium tetroxide.Representative compounds, thus prepared, include:

ethyl 2,3-dicarboXy-5,6-dihydroxy-2-methylnorbornane- 7-acetate,

propyl 2,3-dicarboxy-5,6-dihydroxy-2-propylnorbornane- 7-acetate,

butyl 2,3-dicarboxy-5,6-dihydroxy-2-butylnorbornane- 7-acetate,

isopropylu-butyl-2,3-dicarboxy-5,6-dihydroxy-2-isobutylnorbornane-7-acetate,

isobutyl 2,3-dicarboxy-S,6-dihydroxy-Z-isopropylnorbornane-7-acetate,

hexyl a-pr0pyl-2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate,

heptyl 2,3-dicarboxy-5,6-dihydroxy-2-ethylnorbornane- 7-acetate,

octylot-methyl-2,3-dicarboxy-5,6-dihydroxy-2-propylnorbornane-7-acetate,

pentyl 2,3-dicarboxy-5,6-dihydroxy-Z-ethylnorbornane-7- acetate,

isopentyl 2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate,

methyl a-methyl-2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-acetate,

ethyl a-ethyl-Z,3-dicarboxy-5,6-dihydroxy2-butylnorbornane-7-acetate,

and the like.

EXAMPLE 11 Methyl 2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate acetonide A 128 g. (0.424 mole) quantity of methyl2,3-dicarboxy-5,6-dihydroxy-Z-methylnorbornane 7 acetate was slurried in2 l. of acetone and 160 ml. of 2,2-dimethoxypropane. The slurry wastreated with 4 ml. of 2.4 M hydrogen chloride in anhydrous dioxane,causing the suspended solid to dissolve immediately. After /2 hour, thesolution was evaporated to dryness in vacuo leaving, when completelydry, 140 g. of crystals of methyl2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate acetonidesuitable for further use. A sample was prepared for analysis by onerecrystallization from benzene-acetone; melting point l54155 C.

Analysis.Calcd. for C H O (percent): C, 56.15; H, 6.48. Found (percent):C, 56.25; H, 6.57.

EXAMPLE 12 Methylot-methyl-2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetateacetonide In the manner given in Example 11, methyl a-methyl-2,3-dicarboxy 5,6 dihydroxy-Z-methyl-norbornane-7- acetate was treatedwith 2,2-dimethoxypropane in acetone to give methyla-methyI-Z,3-dicarboxy-5,6-dihydroxy-2- methylnorbornane-7-acetateacetonide.

In the manner given in Example 11, other alkyl 2,3-dicarboxy-S,6-dihydroxy-2-alkylnorborane 7 acetic acid ketals or acetalscan be prepared by reacting an alkyl 2,3-dicarboxy-S,6-dihydroxy-2-alkylnorbornane-7-acetate with a ketone oraldehyde. Representative compounds, thus obtained, include:

The acetonide, methyl ethyl ketal, diethyl ketal, propyl ethyl ketal,formaldehyde acetal, acetaldehyde acetal, and propionaldehyde acetal andthe like of ethyl 2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate,

propyl 2,3-dicarboxy-5,6-dihydroxy-2-propylnorbornane- 7-acetate,

butyl a-propyl-2,3-dicarboxy-6,6-dihydroxy-2-butylnorbornane-7-acetate,

isopropyla-butyl-2,3-dicarboxy-5,6-dihydroxy-2-isobutylnorbornane-7-acetate,

isobutyl 2,3-dicarboxy-5,6-dihydroxy-2-isopropylnorbornane-7-acetate,

hexyl u-propyl-2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate,

heptyl 2,3-dicarboxy-5,6-dihydroxy-2-ethylnorbornane- 7-acetate,

octyl a-methyI-Z,3-dicarboxy-5,6-dihydroxy-2-propylnorbornane-7-acetate,

pentyl 2,3-dicarboxy-5,6-dihydroxy-2-ethylnorbornane- 7-acetate,

isopentyl 2,3-dicarboxy-S,6-dihydroxy-2-methylnorbornane-7-acetate,

methylot-methyl-2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate,

ethyl ethyl-2,3-dicarboxy-5,6-dihydroxy-2-butylnorbornane-7-acetate,

and the like.

"EXAMPLE 13 Methyl 2 methyl 5,6-dihydroxy-2-norbornene-7-acetateacetonide (VII when R, R R and R are methyl; R is hydrogen) A 5.1 g. (15millimoles) quantity of methyl 2,3-dicarboxy 5,6dihydroxy-2-methylnorbornane-7-acetate acetonide was dissolved in 200ml. of pyridinezwater (:10 by volume) and 3.75 ml. of triethylamine. Theresultant solution was electrolyzed using platinum wire mesh electrodesheld between 60 and 90 volts. The reaction temperature was maintainedthroughout at 15-20" C. using a solid carbon dioxide-acetone bath. Theinitial value for the amperage under these conditions was 4. Theamperage was maintained at this value by the gradual addition of asolution of 20.5 g. of methyl 2,3-dicarboxy-5,6-dihydroxy-2-methylnorbornane-7-acetate acetonide in ml. ofpyridinezwater (90:10 by volume) and 3.75 ml. of triethylamine. Theaddition was completed in about 1.5 hours, after which the reaction Wasallowed to proceed till the amperage fell below a value of one (about 5hours total reaction time). The mixture was evaporated to dryness invacuo and the residue was partitioned between 1 N hydrochloric acid andmethylene chloride. The methylene chloride layer Was washed successivelywith 1 N hydrochloric acid, 5% aqueous sodium bicarbonate and saturatedbrine, and dried over anhydrous sodium sulfate. Distillation of themethylene chloride left a dark brown residue which was combined with thecrude residues from two similar runs. Chromatography on 2 kg. of silicagel, eluting with methanolzmethylene chloride (3:97 by volume) gave twocompounds. The faster moving was easily detectable on thin layerchromatography with KMnO -NalO reagent and was found by NMR to be thedesired methyl 2-methyl-5,6-dihydroxy-2-norbornene- 7-acetate acetonide.

The yields of this compound varied from 25% on the scale described aboveto greater than 50% on l-gram runs.

IR spectrum (mineral oil mull): 1735, 1625, 1265, 1200, 1180, 1050,1030, 855.

EXAMPLE 14 Methyl u,Z-dimethyl-S,6-dihydroxy-2-norbornene-7- acetateacetonide In the manner given in Example 13, methyl a,2-dimethyl 2,3dicarboxy 5,6 dihydroxynorbornane-7- acetate acetonide wasdecarboxylated in pyridine-water in the presence of triethylamine, withan electric current, to give methyl a,2 dimethyl5,6-dihydroxy-2-norbornene- 7-acetate acetonide.

In the manner given in Example 13, other alkyl 2,3- dicarboxy 5,6dihydroxynorbornane 7 acetate ketals or acetals can be converted to thecorresponding alkyl 2- alkyl 5,6 dihydroxy 2 norbornene-7-acetate ketalsor acetals 'by means of electric current.

Representative compounds, thus obtained, include:

ethyl a,Z-diethyl-S,6-dihydroxy-2-norborncne-7-acetate acetonide,

propyl a,2-dipropyl-5,6-dihydroxy-2-norbornene-7-acetate acetonide,

butyl a,2-dibutyl-5,d-dihydroxy-2-norbornene-7-acetate acetonide,

isopropyl a,2-dimethyl-5,6-dihydroxy-2-norbornene-7- acetatebenzaldehyde acetal,

isobutyl a-methyl-Z-ethyl-5,6-dihydroxy-2-norbornene-7- ethyla-propyl-2-methyl-5,6-dihydroxy-2-norbornene-7- acetate acetonide,

propyl aisopropyl-2-ethyl-5,6-dihydroxy-2-norbornene-7- acetateacetonide,

ethyl a,2-dibutyl-5,G-dihydroxy-2-norbornene-7-acetate acetonide,

and the like.

What is claimed is: 1. A compound of the formula:

COOR RQ'LH wherein R is alkyl of l to 8 carbon atoms, inclusive, whereinR is alkyl of 1 to 4 carbon atoms, inclusive, wherein R is selected fromthe group consisting of hydrogen and alkyl of 1 to 4 carbon atoms,inclusive, and wherein R and R are selected from the group consisting ofhydrogen, alkyl of 1 to 4 carbon atoms, inclusive, and phenyl, with theproviso that only one of R and R is phenyl.

2. A compound according to claim 1 wherein R, R R and R are methyl andwherein R is hydrogen, and the compound is therefore methyl2-methyl-5,6-dihydroxy-2- nor-bornene-7-acetate acetonide.

References Cited UNITED STATES PATENTS 3,033,877 5/ 1962 Veer 260--345.8

NICHOLAS S. RIZZO, Primary Examiner J. H. TURNIPSEED, Assistant ExaminerUS. Cl. XR.

260395.8, 468 B, 468 R, 514 R, 514 B, 546

